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1 2 The role of vitamins and minerals in modulating the expression of microRNAs 3 Emma L Beckett, Zoe Yates, Martin Veysey, Konsta Duesing and Mark Lucock 4 Table S1: Summary of studies linking modulation of miRNA expression to nutritional status 5 of vitamins and minerals Nutritional status miRNA Serum/plasma 5323p(103) vitamin D Direction Target/Pathway of modulation Human Cohort Studies ↓↑ - 92b 93 138 196a* 320d 423-3p 484 573 589 601 ↓ 5745p(104) ↑ 222(109) ↓ - Zinc depletion 10b 155 200b 296-5p, 373 92a 145 204 211(152) ↓ Parallel decrease in ability of blood cells to produce TNFα in response to inflammatory stimuli Folate intake Methyl donor deficiency let-7a 21 305 genes (299 upregulated and 6 downregulated) differentially expressed Animal Model Studies ↑ - Notes Positive correlation between expression and serum 25hydroxyvitamin D levels miRNAs are differentially expressed between low (less than or equal to 25.5ng/ml) or high (greater than or equal to 31.7ng/ml) Inverse correlation between expression and intake miRNA levels increased again following repletion Methyl donor deficient diet leads to 23 130 190 17-92 Hepatocellular carcinoma after 54 weeks 122(112) ↓ 34a 16a 181a 127(113) ↓ Choline and amino acid deficiency 21 155 221 222(114) ↑ Retinoic acid treatment 9 124a 125b(117, 120) let-7b 16 30a 126 143 322 721 ↓ Vitamin C deficiency ↑ Return to control diet at 36 weeks led to return to normal miRNA profiles and no induction of disease Increased levels of E2F3 All are known tumour and BCL6, proteins suppressor miRNAs known to be regulated by miR-34a and miR127 respectively Correlated with PTEN and C/EBPbeta significant reduction in are tumours suppressor the expression of hepatic genes phosphatase and tensin homolog (PTEN) and CCAAT/enhancer binding protein beta (C/EBPbeta), targets of miR-21 and miR-155, respectively Spinal development Rat model of spina bifida Reduced capacity to oppose oxidative stress Murine ovarian follicular cells in enzyme Lgulono-y-lactone oxidase deficient mice Correlated with reduced plasma cholesterol Synthetic inhibition of miR-122 in mice led to the increase of expression of 108 genes related to lipid metabolism(143,144) ↓ Vitamin E deficiency Vitamin D let7c(131) 122 125b(142) 22(92) ↓ Cell Culture System Studies ↑ Correlates with reduced Expression and reduction proliferation in colon cancer cell lines treatment Folate deficiency Retinoic acid treatment 32(168) ↑ 181a(99) ↓ 26b 182 200b/c let-7(100) ↓ let-7a 15a/b 16 29a/b 34a 130b 125a-5p 124 ↑ Suppressed expression of Bim pro-apoptotic factor Led to the arrest of cell cycle progression in the G1 phase Serum-starvation (low serum content media) increased miRNA expression, vitamin D treatment reverses this Inhibited growth with a higher rate of apoptosis led to accumulation in G0/G1 phase of the cell cycle 290-3p 302a(108) ↓ 222 (109) ↑ 9 103(117) ↑ 152(118) ↑ 29a(123) 142-3p ↑ Induced granulocytic differentiation let-7d/a-3 15a 16-1 107 ↑ Down-regulated Bcl-2 (apoptosis regulator) and Ras ID2, a transcription factor expressed in neural precursor cells, but also up-regulated during tumourigenesis in the neural system DNMT1 of proliferation occurred in a time, dose and VDR dependent manner Induced features of normal monocytes in AML cells Expression occurred in a dose and time dependent manner in Leukaemia cell lines (HL60 and U937) Breast epithelial cell line (MCF12F) Murine embryonic stem cells TK-6 human lymphoblast cell line Treatment leads to differentiation and inhibition of proliferation in neuroblastoma cell lines Neuroblastoma cell line (SK-N-BE) Leukaemia cell lines (HL-60, THP-1 and NB4) NF-κB recruitment on the let-7 cluster Vitamin C treatment Selenium treatment 223(125) 146(130) ↑ Induction of cellular differentiation 34(149) ↑ Positive correlation with p53 expression Periodontal ligament cells (multi-potent population) LNCaP human prostate cancer cell line 1 2 References 3 92. 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